The present invention relates to novel substituted 5-hydroxy-2,3-dihydrobenzofurans and analogs thereof useful as anti-inflammatory agents.
It has been observed that the novel compounds of this invention are active in vitro in both the peritoneal macrophage assay and the polymorphonuclear leukocyte assay for general anti-inflammatory activity. Specifically, they are found to be active in vivo in the mouse ear assay for topical anti-inflammatory agents. Furthermore, these compounds tend to be inactivated in vivo after deeper and longer penetration into the body system and are therefore devoid of any significant adverse side effects normally associated with systemic activity.
Recent studies demonstrated that macrophages participate in the development and progression of chronic inflammatory diseases such as rheumatoid arthritis. During the progression of inflammatory conditions, there is generally an appearance and/or presence of macrophages and lymphocytes, especially macrophages and polymorphonuclear leukocytes. Macrophages are known to secrete various products in response to inflammatory stimuli. For example:
(1) Neutral proteases--the destructive peptide bond cleaving enzymes which have been shown to be directly involved in rheumatoid cartilage destruction; and
(2) Prostaglandins (PG) (e.g., E.sub.2 and I.sub.2 by mouse peritoneal macrophages) and other arachidonic acid derivatives derived from both the cyclooxygenase and the lipoxygenase pathways.
These arachidonic acid oxygenation products have been identified as the critical mediators of various acute inflammatory conditions.
Accordingly, pharmacological agents which inhibit the formation or the release of a mediator and thereby interfer with the function of macrophages of polymorphonuclear leukocytes may also be effective anti-inflammatory agents. Generally such a pharmacological agent can be used in the treatment of rheumatoid arthritis, emphysema, bronchial inflammation, osteoarthritis, acute respiratory distress syndrome, spondylitis, lupus, gout, psoriasis and other inflammatory diseases.
Regarding the topical mouse ear assay, it has been previously established that classical nonsteroidal anti-inflammatory agents such as indomethacin and steroidal anti-inflammatory agents such as dexamethasone are active in this assay.
Normally, anti-inflammatory agents which are not significantly systemically active are advantageous because they do not show the kind of adverse effects, e.g., gastrointestinal ulcerations and bleeding that often plagued users of systemic NSAIAs (non-steroidal anti-inflammatory agents). Accordingly, an object of this invention is to provide novel 5-hydroxy-2,3-dihydrobenzofuran derivatives and analogs thereof for the treatment of inflammatory conditions and prusitus such as sunburn, erythema, eczema, contact dermatitis, allergic dermatitis, and psoriasis. It is also intended that these compounds be used for the treatment of peridontal disease and for the treatment of inflammatory bowel disease.
Another object of this invention is to provide appropriate processes for the preparation of the subject novel compounds.
Still a further object of the present invention is to provide a pharmaceutically acceptable composition containing an effective amount of the active compound for the treatment of various inflammatory conditions.
Finally, it is the ultimate object of this invention to develop a method of treating inflammation via the administration of a therapeutically effective amount of the novel compounds or pharmaceutically acceptable composition thereof to a mammalian species in need of such treatment.